In addition to direct targeting and repressing mRNAs, recent studies reported that microRNAs (miRNAs) can bridge up an alternative layer of post-transcriptional gene regulatory networks. The competing endogenous RNA (ceRNA) regulation depicts the scenario where pairs of genes (ceRNAs) sharing, fully or partially, common binding miRNAs (miRNA program) can establish coexpression through competition for a limited pool of the miRNA program. While the dynamics of ceRNA regulation among cellular conditions have been verified based on in silico and in vitro experiments, comprehensive investigation into the strength of ceRNA regulation in human datasets remains largely unexplored. Furthermore, pan-cancer analysis of ceRNA regulation, to our knowledge, has not been systematically investigated.

Background: ADH1B rs1229984 and ALDH2 rs671 are the specifically prevalent functional variants in the East Asians. These variants, which result in a dramatic change in enzyme activity, are highly associated with alcohol‐related disorders and cancer. Previous studies focusing on the additive and synergic effects of the variants are few and inconsistent. The aim of the research was to evaluate the associations of ADH1B rs1229984 and ALDH2 rs671 with the risks of alcohol‐related disorder and cancer.Methods: This cohort study enrolled 42,665 participants from the Taiwan Precision Medicine Initiative database, including 19,522 and 20,534, ADH1B and ALDH2 carriers, respectively. The associations between the two variants and cancer risk were analyzed by univariable and multivariable logistic regression.Results: Compared with the noncarriers, the ADH1B rs1229984 variant had a stronger effect on alcohol‐related disorders and was related to an increased risk of alcohol‐related cancers. The CC genotype of ADH1B rs1229984 was significantly associated with cancer of the larynx, pharynx, and nasal cavities [odds ratio (OR) = 1.56, p = 0.0009], cancer of the pancreas (OR = 1.66, p = 0.018), and cancer of the esophagus (OR = 4.10, p < 0.001). Participants who carried the rs1229984 TC/CC and rs671 GG genotypes were at higher risk of esophageal cancer (OR = 3.02, p < 0.001). The risk of esophageal cancer was increased by 381% (OR = 4.81, p < 0.001) in those carrying the rs1229984 TC/CC and rs671 GA/AA genotypes.Conclusion: rs1229984 and rs671 are common and functionally important genetic variants in the Taiwanese population. Our findings provide strong evidence of additive and synergic risks of ADH1B and ALDH2 variants for alcohol‐related disorders and cancer. The results suggested that are reduction in alcohol consumption should be advised as a preventive measure for high‐risk patients carrying ADH1B rs1229984 C or the ALDH2 rs671 A allele.

Targeting metabolic reprogramming is an emerging strategy in cancer therapy. However, clinical attempts to target metabolic reprogramming have been proved to be challenging, with metabolic heterogeneity of cancer being one of many reasons that causes treatment failure. Here, we stratified non-small cell lung cancer (NSCLC) cells, mainly lung adenocarcinoma, based on their metabolic phenotypes and demonstrated that the aerobic glycolysis-preference NSCLC cell subtype was resistant to the OXPHOS-targeting inhibitors. We identified that monocarboxylate transporter 4 (MCT4), a lactate transporter, was highly expressed in the aerobic glycolysis-preference subtype with function supporting the proliferation of these cells. Glucose could induce the expression of MCT4 in these cells through a ΔNp63α and Sp1-dependent pathway. Next, we showed that knockdown of MCT4 increased intracellular lactate concentration and induced a reactive oxygen species (ROS)-dependent cellular apoptosis in the aerobic glycolysis-preference NSCLC cell subtype. By scanning a panel of monoclonal antibodies with MCT4 neutralizing activity, we further identified a MCT4 immunoglobulin M (IgM) monoclonal antibody showing capable anti-proliferation efficacy on the aerobic glycolysis-preference NSCLC cell subtype. Our findings indicate that the metabolic heterogeneity is a critical factor for NSCLC therapy and manipulating the expression or function of MCT4 can be an effective strategy in targeting the aerobic glycolysis-preference NSCLC cell subtype.

The natural course of chronic hepatitis B (CHB) infection and treatment response are determined mainly by the genomic characteristics of the individual. We investigated liver gene expression profiles to reveal the molecular basis associated with chronic hepatitis B and IFN-alpha (IFNα) treatment response in CHB patients. Expression profiles were compared between seven paired liver biopsy samples taken before and 6 months after successful IFNα treatment or between pretreatment biopsy samples of 11 IFNα responders and 11 non-responders. A total of 132 differentially up-regulated and 39 down-regulated genes were identified in the pretreated livers of CHB patients. The up-regulated genes were mainly related to cell proliferation and immune response, with IFNγ and B cell signatures significantly enriched. Lower intrahepatic HBV pregenomic RNA levels and 25 predictive genes were identified in IFNα responders. The predictive gene set in responders significantly overlapped with the up-regulated genes associated with the pretreated livers of CHB patients. The mechanisms responsible for IFNα treatment responses are different between HBV and HCV patients. HBV infection evokes significant immune responses even in chronic infection. The up-regulated genes are predictive of responsiveness to IFNα therapy, as are lower intrahepatic levels of HBV pregenomic RNA and pre-activated host immune responses.

Background: Single-nucleotide polymorphism (SNP) arrays are an ideal technology for genotyping genetic variants in mass screening. However, using SNP arrays to detect rare variants [with a minor allele frequency (MAF) of <1%] is still a challenge because of noise signals and batch effects. An approach that improves the genotyping quality is needed for clinical applications.Methods: We developed a quality-control procedure for rare variants which integrates different algorithms, filters, and experiments to increase the accuracy of variant calling. Using data from the TWB 2.0 custom Axiom array, we adopted an advanced normalization adjustment to prevent false calls caused by splitting the cluster and a rare het adjustment which decreases false calls in rare variants. The concordance of allelic frequencies from array data was compared to those from sequencing datasets of Taiwanese. Finally, genotyping results were used to detect familial hypercholesterolemia (FH), thrombophilia (TH), and maturity-onset diabetes of the young (MODY) to assess the performance in disease screening. All heterozygous calls were verified by Sanger sequencing or qPCR. The positive predictive value (PPV) of each step was estimated to evaluate the performance of our procedure.Results: We analyzed SNP array data from 43,433 individuals, which interrogated 267,247 rare variants. The advanced normalization and rare het adjustment methods adjusted genotyping calling of 168,134 variants (96.49%). We further removed 3916 probesets which were discordant in MAFs between the SNP array and sequencing data. The PPV for detecting pathogenic variants with 0.01%10,000 are available. The results demonstrated our procedure could perform correct genotype calling of rare variants. It provides a solution of pathogenic variant detection through SNP array. The approach brings tremendous promise for implementing precision medicine in medical practice.

Recent studies illuminated a novel role of microRNA (miRNA) in the competing endogenous RNA (ceRNA) interaction: two genes (ceRNAs) can achieve coexpression by competing for a pool of common targeting miRNAs. Individual biological investigations implied ceRNA interaction performs crucial oncogenic/tumor suppressive functions in glioblastoma multiforme (GBM). Yet, a systematic analysis has not been conducted to explore the functional landscape and prognostic significance of ceRNA interaction. Incorporating the knowledge that ceRNA interaction is highly condition-specific and modulated by the expressional abundance of miRNAs, we devised a ceRNA inference by differential correlation analysis to identify the miRNA-modulated ceRNA pairs. Analyzing sample-paired miRNA and gene expression profiles of GBM, our data showed that this alternative layer of gene interaction is essential in global information flow. Functional annotation analysis revealed its involvement in activated processes in brain, such as synaptic transmission, as well as critical tumor-associated functions. Notably, a systematic survival analysis suggested the strength of ceRNA-ceRNA interactions, rather than expressional abundance of individual ceRNAs, among three immune response genes (CCL22, IL2RB, and IRF4) is predictive of patient survival. The prognostic value was validated in two independent cohorts. This work addresses the lack of a comprehensive exploration into the functional and prognostic relevance of ceRNA interaction in GBM. The proposed efficient and reliable method revealed its significance in GBM-related functions and prognosis. The highlighted roles of ceRNA interaction provide a basis for further biological and clinical investigations.